We report an unusual case of acute biphenotypic leukemia with trisomy 4. A 22-year-old woman presented with acute leukemia characterized by the presence of two cell populations (prothymocytic and myeloblastic). The leukemic cells were resistant to standard induction chemotherapy and were cleared from the bone marrow only after a salvage chemotherapy regimen. To our knowledge, this is the fourth reported case of acute biphenotypic leukemia with trisomy 4 and perhaps the first case with T-lineage markers and acute myelocytic leukemia.